Tertiary-aminoalkyl-alpha-arylalpha-(4-quinolyl) acetates and amides and their preparation



Patented Sept. 25, 1951 TERTIARY-AMINOALKYL-ALPHA-ARYL ALPHA-(4-QUINOLYL) ACETATES AND AM'IDES AND THEIR PREPARATION Alexander R.Surrey, Albany County, and Royal A. Cutler, Rensselaer County, N. Y.,assignors to Sterling Drug Inc., Wilmington, Del., a cora poration ofDelaware No Drawing. Application May 28, 1948,

. Serial No. 29,937

This invention relates to quinoline compounds and to processes ofpreparing the same.

More particularly, this invention relates to basicalpha-aryl-alpha-(4-quinolyl) acetic acid esters and amides, to additionsalts thereof, to intermediates therefor, and to processes of preparingsaid basic compounds and intermediates therefor.

More particularly the basic compounds of this invention are those havingthe formula QCH(A) COYXB where Q is a 4-quinolyl radical, A is anarylradical, Y is O, NH or N- (lower alkyl) X is a lower alkyleneradical, and B is alower aliphatic tertiary-amino radical. Thesecompounds are of interest as pharmaceutical agents.

In the above formula the lower aliphatic tertiary-amino radical,designated as B, comprehends lower dialkylamino radicals illustrated bysuch examples as dimethylamino, diethylamino, ethylmethylamino,di-n-butylamino, and. the like; and lower saturated lN-heterocyclicgroups illustrated by examples such as l-piperidyl,3-methyl-1-piperidyl, 1,-pyrro1idyl, 4-morpholinyl,2,6-dimethyl-1-piperidyl, and thelike. It follows that BH designates alower aliphatic secondary-amine as illustrated by diethylamine,di-n-butylamine, morpholine, 2-methyl-l-piperidine, and the like. Thelower alkylene group, designated as X, preferably contains 2-6 carbonatoms, and includes such examples as 1 and the like. It follows that BX-designates" a lower aliphatic tertiary-aminoalkyl radical where B and Khave the meanings h'ereinabove described. Examples of such loweraliphatic ter-' tiary-aminoalkyl radicals include Z-dimethyllamino-l-propyl, Z-diethylaminoethyl, 2-(ethyl--- methylamino) ethyl, 3-(di-n-butylamino) propyl, 4- (1 -piperidyl) butyl, 5- (2 -methy1-1-piperidyl) 2-pentyl, 2-(1-pyrrolidyl) -ethyl, 3- (4-morpho linyl)propyl, 2-(2-diethylaminoethoxy) ethyl, 2-(3-dimethylaminopropylmercapto) ethyl, and the like 20 Claims. (Cl.260-287) The aryl radical, designated as A, is one of preferably 6-10carbon atoms. The aryl radical can be substituted by such groups ashydroxyl; alkoxyl such as methoxyl, ethoxyl, etc.; dialkylamino such asdimethylamino; halogen such as chloro,

bromo, or iodo; lower alkyl such as methyl, ethyl, butyl, etc.; andother groups which the chemist appreciates will be unafiected byfthereaction conditions used in the preparation of the basic compounds ofour invention.

. It is to be understood that the termfa 4-quinolyl radical(designated'as Q) as used in this specification and in the appendedclaims is generic, and includes 4-quinolyl radicals wherein thequinoline nucleus may be substituted by one or more of such groups as:halo, including chloro, bromo, iodo, and fluoro; lower alkyl, includingmethyl, ethyl, propyl, amyl, andthe like; hydroxy; lower alkoxy',including 'methoxy, ethoxy, propoxy, and the like; aryloxy, such asphenoxy; aralkoxy, such as benzyloxy; trihaloalkyl, such astrifluoromethyl; nitro; amino; substitutedamino, such as acetylamino,ethylamino, dimethylamino, benzylamino, and the like; and othersubstituents.

-As illustrative of our invention thefollowing specific compounds arepresented:

1. 2-di-n-butylaminoethyl alpha-(3-ethoxyphenyl) alpha-(6-methoxy-4-quinolyl) acetate, so

HC 0 O CHzCHzN(CHzCHgCH2CH3)2 CHaQ N 2. 3-(I-piperidyDpropylalpha-(3,4-dichloro phenyl) -alpha- (6,8- dichloro-4-quinolyl) acetate,

3. 4-dimethylaminobuty1 alpha-phenyl-alpha- (4-quinolyl) -acetate,

HO O O CH2CH2CHiCH2N(OHa)2 5. s (2 methyl 1 piperidyhpropylalphaphenyl-alpha- (3-nitro-4-quinolyl) acetate,

CHz-CH:

CH2 CHE-C HO O O CHzOHzCHzN 6. N (2 4 morpholinyl) ethyli-alpha 4-methylphenyl) alpha (3,6,7-trimethyl-4-quinolyl) acetamide,

CHC ONHCHzOHzN CH CH3 GET-C 7. N (3 (2 methyl 1 pyrrolidybprop l alpha(4 dimethylaminophenyl) alpha-(7 phenoxy-4-quinolyl) acetamide,

mom):

for preparing the above compounds. esses are presented in the followingchart, where- 8. N ethyl N (2 dimethylaminoethyD- alpha phenyl alpha (7chloro 4 quinolyl) acetamide,

Our invention further comprehends processes These procin Q, A, Y, X andB have the meanings hereinabove specified, Z stands for halogen, and Rstands for H or lower alkyl.

CHART I CHCN III QZ ACHzCN 1 II Q cuooNm \CHCO O-alkyl Q V Q (5) BXOH(6) Biz-Nuns \CHC O OXB Q Q VII' Step (1) of Chart I involves thecondensation of a i-haloquinoline (I) with an arylacetonitrile (II) inthe presence of a strong base toyield an alpha aryl alpha (4quinolybacetonitrile (III). e For example, alpha-phienyl-alpha-(5-chloro-4-quinolyl) acetonitrile is prepared by condensingphenylacetonitrile with 4,5-dichlor0quinoline in the presence of sodiumamide. Other basic condensation agents, e. g. potassium amide, sodiumhydride, phenyllithium, and the like, can be used in place of sodiumamide. Weprefer to use sodium amide as the base because of itsavailability and low cost. We found that excellent results were obtainedin this condensation when about two moles of sodium amide and two molesof arylacetonitrile were employed per one mole of 4-ha1oquinoline inbenzene as the solvent with the reaction temperature being kept below 35C. The condensation can also be run using other ratios of reactants, orhigher reaction temperatures, but with a sacrifice in yields. Further,solvents other than benzene, such as toluene, xylene,ether, dioxane, andthe like can be used. Q I

The. intermediate 4-haloquinolines (I) are generally well known to thoseskilled in the art; for representative literature references see: Surreyet al., J. Am. Chem. Sod-68,113, 1244, and 2570 (1946); Steck et al.,ibid. 129, 132, 380, and 1241 (1946); Riegel et al., ibid. 1229; Bakeret al., ibid. 1267; Mosher et al., ibid. 69, 303 (1947); Bachman et al.,ibid. 365; Snyder et al., ibid 3'71; and Clinton .et al., ibid. 704,Some -haloquinolines that are useful intermediates in the prep-l.

, 3-methyl-4-chloro-'7-iodoquinoline i 3-methyl-4-chloro-8-iodoquinoline3-methyl-4,5-dichloroquinoline 3-methyl-4,7-dichloroquinoline I3-methyl-4-chloro-l-bromoquinoline 3-methyl-4-chloro-6-bromoquinoline3-methyl-4-chloro-fi-ethoxyquinoline 3,6-dimethyl-4-chloroquinoline3-methyl-4,8-dichloroquinoline G-methyli-chloro-B-methoxyquinoline3,8-dimethyl-4-chloroquinoline 4,7-dichloroquinoline4-chloro-7-bromoquinoline 4-chloro-7-iodoquinoline4,7-dichloro-6-methoxyquinoline 4;,5-dichloroquinoline 3-nitro-4-chloroquinoline 3-amino-4-chloroquinoline 4-chloro-'l-fluoroquinoline4-chloro-'7-trifiuoromethylquinoline 4,7-dichloro-5-methoxyquinoline4-chloro-l-phenoxyquinoline 3,4-dibromoquinoline4-chloro-6-nitroquinoline Thealpha-aryl-alpha.-.(4-quinolyl)acetonitrile (III) can be hydrolyzed,through step (2) of Chart I, to an alpha-aryl-alpha- (4-quinolyl)acetamide (IV) or, through step (3), to a lower alkyl alpha-aryl-alpha-(4-guinolyl) -acetate (V);

Step (2) can be carried out by various means. We found that quantitativeyields of amide, IV, were obtained by allowing a concentrated sul-'furic acid solution of the nitrile, III, to stand overnight at roomtemperature. The amide, IV, is also formed when the nitrile, III, isrefluxed with aqueous potassium hydroxide or with sodium hydroxide inabout 70% ethanol. Further, quantitative yields of the amide, IV,areobtained when a solution of the nitrile, III,"in absolute methanol istreated at room temperature for about six hours with dry hydrogenchloride. The same results are obtained by substituting for "absolutemethanol, dry chloroform containing absolute ethanol, and then, afterthe'treatment with hy drogen chloride, allowing the resulting solutionto stand for three days. The reaction using'ab solute methanol as the's'olvent can be carried out at refluxing temperature, however the yieldof amide, IV, is low. As afspecific 'illustr'ationof step (2),,alpha-(4-methoxyphenyl) alpha-(6- methoxy-4-quinolyl) acetonitrileishydrolyz'ed 'to alpha (4-methoxyphenyl) alpha- (G-methoxyi-quin'olyl)acetamide.

The alcoholysis of the nitrile, III, to the lower alkyl ester, V,designated as step (3 in Chart I, was found, in our hands, not to takeplace under ordinary conditions customar for conversionjof nitriles toesters. For examplejQphenylacetonitrile is converted in good yield ethylphenyl= acetate'by refluxing the nitrile for three hours withconcentratetd sulfuric acid in absolute etli-' anol (Reactions ofOrganic Compounds, Hickinbottom, page 251, Longmans, 1945). However,when the same conditions are applied in an attempted hydrolysis ofalpha-phenyl-alpha-(7- chloro-4-quinolyl)acetonitrile, most of thestarting nitrile is recovered after refluxing for four hours. Refluxingthis same nitrile for about twenty-two hours with concentrated sulfuricacid and ethanol results in a quantitative yield or 7-1chloro-i-benzylquinoline. Repetition of the latter experiment at lowertemperatures (-50 C.) for about twenty-:two hours gives only unchangednitrile. The same results are obtained by allowing the solution of thenitrile, sulfuric acid, and ethanol to stand for six weeks at roomtemperature.

.Ethyl 4-quinolylacetate has been prepared in good yield by refluxing4-quinolylacetonitrile in absolute ethanol for four hours while passingdry hydrogen chloride through the solution (Borsche and Butschli, Ann.529, 266 (1937)). A similar procedure applied toalpha-phenyl-alpha-("lchloro-4-quinolyl)acetonitrile, using methanol asthe solvent, yields a small amount of thecorresponding amide plus theunchanged nitrile.

- Increasingthe reflux period to eight hours and V as using ethanol asthe solvent gives principally 7,-chloro-4-benzylquinoline. We did havesuccess in performing step (3) by using hydrogen chloride inaqueous-alcoholic media at lower temperatures. Thus, as an illustrativecase, alpha-phenyl-alpha-('7-chloro-4- quinolyDacetonitrile, is addedto' a cooled, previously saturated hydrogen chloride solution of onepart water in three parts of ethanol, The passage of hydrogen chloridethrough thejsolution is continued for five or six hours at roomtemperature and the reaction mixture allowed to stand for varyinglengths-of time. In each of these experiments some of the correspondingamide is obtained together with some of the corresponding ethyl ester,the amount of amide varying inversely with the length of time'ofstanding; For example, four hours of standing yields 20-30% of theester, and the remainder consisting of the amide; three days "ofstanding gives 40% of the ester and two weeks, 70%."

-'Step (4) of Chart I is carried out successfully employing conditionsfound satisfactory in exeouting step (3)." Thus, under such'conditionsusing astanding period of about three weeks and methanol as the alcohol,a 56% yield of methyl alpha phenyl alpha (7-chloro-4-quinolyl) acetateis obtained from the corresponding disubstituted-acetamide.

The alkyl" alpha-aryl-alpha- (4-quinolyl) acetate, V in Chart I, can beconverted, by step (5), into the corresponding tertiary-aminoalkylesters or;-by-':step (6), intomthe corresponding N-(tertiary-aminoalkyl)amides. I The basic esters, VI, are formed whe n V is treated with alower aliphatic tertiary-aminoalkanol, designated as BXOI-I, where BX-is a lower aliphatic-tertiaryaminoalkyl radical as described hereinaboveand the basic amides, VII, are obtained when V is treated'with a loweraliphatic tertiary-aminoalkylamine, designated as BXNHR, where R is H orlower alkyl. As specific illustrations, 3-(1- piperidyl) -propylalpha-phenyl-alpha-(5-chloroifquinolybjacetate is formed when thecorresponding lower alkyl (preferably methyl or 'ethyl) ester treatedwith-3-(l-piperidyl) propanol; N-'

(2:;(4morpiholir'1yl)ethyl) alpha-phenyI-aIpha', (4-'quinolyl)"acetamideis formed by treating the correspondinglower"-alkyl ester with.2-(4-morpholinyll-ethylamine; N methyl-N-(Z-diethylaminoethyl)-alpha-phenyl-alpha- (7 chloro 4- quinolyDacetamide is obtained from thecorresponding lower alkyl ester and N,N-diethyl-N-methyl-'1,2-ethylenediamine. g

In addition, our invention comprehends a method of preparing 4-(arylmethyl) quinolines 01' the general formula QCHzA, where Q and Ahave the meanings specified above. This method, involves removal of theCN'group ofcompounds havingtheformula, ACH(Q) CN (III in Chart I) theremoval taking place in two steps, namely: the hydrolysis otthenitrilegroup to a carboxyl group, and the eliminationof carbon dioxidefrom the molecule. Quantitative yields are obtained under variousconditions e. g.. by refluxing the -.nitrile, 'III, with about 60%aqueous sulfuric acid for about one hour; or by refluxing the nitrilewith concentrated sulfuric acid in ethanol for about twentytwo hours; orby refluxing the nitrile in absolute ethanol for about eight hourswhilepassing dry hydrogen chloride through the solution. Such treatmentof. alpha-phenylalpha-(4.- -quinolyl) -acetonitr ile yields4-benzylquinoline. This compound, .4-benzylquinoline, has been reportedinthe literature, however, the methods of preparing it have beenfarfrom, be ing satisfactory. ,It was first preparedby Rabe and Pasterna'ck(Ber. 46, 1029 (1913)), who isolated it asa by-product from the actionof benzylrnagnesium chloride on 4-cy'anoquinoline. Bergman and Rosenthal(J. prakt. Chem. 135. 275 (1932) obtained it in small yield from theaction of benzylmagnesium chloride on 'quinoline, 2-benzylquinolinebeing the main product. In addition, Bergstrom (J; Org. Chem. 11,55(1946)) reported 1 its preparation in 37% yield by the action'ofchlorobenzene' on lepidine illthe presence of potassium amide in liquidammonia. Now, by our "abovedescribed method, it is possible to obtainthis compound, as well as other d-arylm'ethylquinolines, in excellentyields. Also encompassed within the scope of our invention are salts ofthe basic compounds", VI and VII, derived from non-toxic inorganic ororganic acids. Among theacids which may be employed to form the saltsare hydrochloric acid, phosphoric acid, sulfuric acid, sulfamic acid,tartaric acid, citric acid, benzoic acid, and the like. Also included inour invention are quaternary salts of these basic esters and amides (VIand VII) derived from esters of inorganicacids, such as methyl iodide,ethyl bromide, benzyl chloride, andthelike. a

The following examples will further illustrate specific embodiments-ofour-invention.

. EXAMPLES- I. AZpha-aryZ-alpha (at-quinolyllacetonitriles Theintermediate alpha-aryl-alpha-(4-quinolyl) acetonitrile designated asIII in Chart I are prepared by condensing a 4-haloquinolinewith anarylacetonitrile. in the presence ofa strong base. The followingprocedure where aryl is phenyl is illustrative of this method: 110 g.(2.6 moles) of sodium amide is added to a Well stirred, ice-cooledsolution of 260 g. (2.2 moles) of phenylacetonitrile in one liter of drybenzene contained in a flask fitted with a soda-lime tube. Thetemperature rises gradually to35 C. with the color of the solutionchanging from a .pale

yellow to a deep reddish-black. After stirring for an hour, one mole ofthe 4-haloquin01ine (preferably where halo is chloro because of ease ofpreparation) is added in small portions at a rate suflicient to maintainthetemperature at 25-30 C. with strong external cooling. After theaddition has been complete, the ice bath is removed and the reactionmixture stirred at room temperature for two hours. The bright red sodiumsalt of the product and unchanged sodium amide are decomposed by thecautiou dropwise addition of water. The light reddish-orange benzenelayer is washed once'with water followed by extraction with dilute hydochloric acid. Ice is added to the acid. extracts and the free baseliberated by theaddition of concentrated ammonium hydroxide. In somepreparations the product separates as-a solid at this stage and iscollected by filtration. In other preparations the free base separatesas an oil which is taken up in an appropriate solvent such aschloroform, and the resulting solution dried 'over anhydrous calciumsulfate. Removal of the solvent by distillation yields a viscous oilwhich, on triturating with a solvent such as ether,- solidifies in mostinstances. When such treatment does not yield a solid, the oil isdistilled in vacuo, and theresulting distillate crystallizes whentriturated with a solvent such as a mixture of ether andn-pentane; Thecrude solids are obtained in practically quantitative yields and areused insubsequent-reactions without further purification. Analyticalsamples are obtained by'recrystallization from petroleum ether.

Compounds prepared in this manner. include those having the formula: 1 II CaHs CHCN where X has the following meanings:

. Crude oil after removal of chloroform is distilled at 0.1 micron, B,P. C. Distillate crystallizes from mixture of'n-pentane and ether.-

Crude product separates as a pale yellow solid on addi- 1011t0fconcentrated ammonium hydroxide to acidic exrac Crude viscous oil afterremoval of chloroform crystallizeson triturating with ether.

II. Alpha-aryZ-alphm (at-quinolyl) actamides The alpha-aryl-alpha-(l-quinolyl) acetamides designated as IV in Chart I are prepared byhydrolyzing the corresponding disubstituted-acetonitriles conditions.

Excellent yields of these amides are obtained by hydrolysis of thecorresponding nitriles with concentrated sulfuric acid at roomtemperature: One part by weight of the alpha-aryl-alph (4-quinolylacetonitrile is dissolved in four volumes of concentrated sulfuric acid,and after standing overnight at room temperature the solution is pouredonto ice containing an excess of ammonium hydroxide. obtained inquantitative yields. Recrystallization from lower alkanols gives whitecrystalline solids.

These'alpha aryl alpha l-quinolyl) acetamides also can be prepared ingood yields by alkaline hydrolysis of the corresponding acetonitriles, 0external c olin as illustrated by the following specific example: Amixture of g. of alpha-phenyl-alpha- (I-chloro- 4-quinolyl)acetonitrile, 5 g. of pellet sodium hydroxide, and 40 ml. of 75% ethanolis refluxed under various sets of reaction 5 phenyl). samba-(6.8fidichloro 4 duinolyl) acetamide; alpha- (3;4 dichlorophenyl) V-a1pha-(3-nitro -4-quinolyl) acetamide; alpha- (4-methoxy phenyl) alpha 6methoxy 4 quinolyllacetamide; and the like. V ing-mm .alkyldZpha-aryl-alp'ha-(4 quinolyl)- ametates 1 1 These esters designated asV in Chart I are 10 preparedfrom either the corresponding nitrilesdescribed in section I or the corresponding amides described-in sectionII.- I

From the nitriles the esters can be produced by using hydrogen chloridein aqueous alcoholic me- The 1m amides are dia at lower temperatures.The following procedure foricompounds where the alpha-aryl groupisphenyl-is illustrative: A solution of one part by 'volume of'water in3 parts by volume of methanol saturatedwith gaseous hydrogen chloridewith The ice bath .is removed and one part by weight of analphaphenyl-a1pha-(4-quinolyl) acetonitrile added at 10-15 ,0. .As theaddition of hydrogen chloride .iscontinued the temperature rises to 35C. and

for six hours. As the reaction proceeds the deep the solid soondissolves completely to form a blood red solution becomes almostcolorless and a solid separates in the form of pale pink needles;

yield, 4.6 g. Treatment of this material with dilute hydrochloric acidgives a white amorphous clear yellow solution. When the lrquinolyl groupis 'l-chloro-l-quinolyl, the white hydrochloride of alpha-phenyl-alpha-(7 -chloro-4-quinolyl acetonitrilesoon separates and graduallyredissolid which is alpha-phenyl-alpha-(7-ch1orosolves over a period ofabout two hours. The

quinolyl) -acetamide.

Quantitative yields of these di-substitutedacetamides are also obtainedby refluxing the corresponding nitriles for seven hours with hydrogenchlorideis bubbled slowly through the solution-for a total of five orsix hours. The resulting solution is stoppered and allowed to stand forvarying amounts of time at room temaqueous potassium hydroxide. In thisprocedure 35.p ,1-, Asester formation occurs ammonium 'no intermediatesalts are isolated.

The amides are also formed by the following procedure as illustrated bythe following specific preparation: Dry hydrogen chloride is passedtonitrile in 50 ml. of dry chloroform containing 2 ml. of absoluteethanol. The color of the solution changes from a light orange to a deepred chloride separates. The, timerequired for the first appearance ofthissalt serves as a rough guide of the rate of esterification. The timerequired for the appearance of ammonium chlointo an ice-cooled solutionof 5 g. of alpha- 40 ride f different starting a1pha pheny1 a1pha phenylalpha ('7 chloro 4 quinolyl) ace- (4-quinolyl) -acetonitriles are asfollows: 2 -3 I 7 hours where the 4-quinolyl radical is 4-quinolyl;

10- 12 hours, where 7-chloro-4-quinolyl; and about one week, where5-chloro-4-quinolyl. The

and finally to a pale yellow color. After about 2145 reaction mixture isworked up by pouring into 20 minutes the reaction flask is fitted with adrying tube and allowed to stand at room-temperature for three days.Thereby is obtained 6 g. of the white crystalline solid,alpha-phenyl-alpha- (7-chloro-4-quinolyl) acetamide. samplerecrystallized from butanol melts at 283-284 C. with decomposition.

Still another method for preparing these amides is illustrated by thefollowing specific preparation: A suspension of 5 g. of alphaphenylalpha (7 chloro 4 quinolyl) acetonitrile in 20 ml. of absolute methanolis treated with a stream of hydrogen chloride for six hours withoutexternal cooling. After a short time dissolution occurs and thehydrochloride of the starting acetonitrile separates to form a thickmass. This gradually redissolves, however before complete dissolutionoccurs, another solid An analytical ice water and liberating the esterwith aqueous sodium hydroxide in the presence of chloroform, care beingtaken to keep the solution cooled by the addition of ice. Filtration atthis point removes most of the amide present. The chloroform layer isseparated and dried with anhydrous calcium sulfate. Evaporation of thechloroform yields the desired ester. The crude product is freed fromsmall amounts of the corresponding amide present by dissolving in hotpetroleum ether, filtering with charcoal, seeding, and allowing to cool.The esters are recrystallized from an appropriate solvent such aspetroleum ether or an alkanol to give white crystalline solids. -,Themelting points of the resulting purified methyl alpha-phenyl-alpha-(4-quinolyl) acetates are as follows: Where the 4-quinolyl radical is4-quinolyl, -62.2 C. (corr.; from petroleum ether); where5-chloro-4-quinolyl, 115.4-1l6.6

C. (corr.; from methanol); and where 'Z-chloro- 4-quinolyl, 129.4l3l C.(corr.; from petroleum ether).

The crude yields of methyl alpha-phenyl- 1 'alpha-(4-quinolyl) acetatesare: Where the 4- quinolyl group is 4-quinolyl, 90% after standingseventeen days; where '7-chloro-4-quinolyl, 40% after three days andafter two weeks; where 5-chloro-4-quinolyl, 56% after five weeks (yield267-268 C. (from butanol) alpha@.(4chloro-- 1| after recrystallizationfrom n-heptane).

when ethanol is substituted form ethanol in'the above procedure. j Forexample, the-yield of ethyl 'alphaphenyl-alpha-(7 -chloro--quinolyl)phen ylacetate, after the reactionmixture stands for three days, is 54%,and the melting point is 127.4-128.4 0. (corn; from petroleum ether).Other lower alkyl estersare formed when the above procedure isfollowedbut usingother lower alkanols in place of methanol. For example, whenthe alkanol is n-butanol and the starting nitrile isalpha-phenyl-alpha-(7-chl0ro-4-quinolyl)acetonitrile-, the resultingester-is n-butyl alpha phenylalpha- (I-chloro-A-quinolyi) acetate.

Other esters prepared according to the above procedure include: methylalpha (4- chlorophenyl) -alpha- (6,81dichloro-4 quinolyl) acetate;

methyl alpha-(3,4-dichlorophenyl)-alpha- (3 -nitro-4-quinolyl) acetate;ethyl alpha- (4-methoxyphenyl) alpha (6 methoxy 4 quinolyDacetate; andthe like. r

These intermediate-lower alkyl alpha-aryl-(iquinolyl) acetates also areprepared byhydrolyzing the corresponding amides under the same reactionconditions described above the hydrolysis of the correspondingnitriles.As illustrative, methyl alpha phenyl-alpha-('Z-chloroiquinolyDacetate isprepared from alpha-phenyl- -alpha (T-chioro--quinolyl)aeetamideusingthe same procedure outlined above in a the hydrolysis of thecorresponding -nitrile.: The yield of the crude ester, after-thereaction mixture has stood for three weeks, is 56%, or lowerthan thatobtained from the nitrile. The yieldis lower prob.-

ably because the amide fails to dissolve completely under the reactionconditions.-

IV. Tertiary dminhdllcyi ..clphaelcrrule.alpha; (4

. ,quinolylmcemtescnd salts...thereo1f The lower aliphatictertiary-aminolkayl alphaaryl-alphai-quinolyll acetates designated as VIin Chart '1 are prepared by treating a correspondinglower alkyl esterwith a; lower aliphatic tertiary-aniinoalkanol' The following procedure.cool reaction mixture is diluted with arr-equal volume of etherandextracted with dilute aqueous hydrochloric acid. The extractis madejust alkaline to. litmus. with.10.% sodium hydroxide solution andextracted With'etherto. remove any unchanged ester together withthesmall amount of the 4-benzylqui-nolineiormed due tothereaction of thesodium alkoxide presents The aqueous layer is, made alkaline tophenolphthalein with sodium hydroxide. solutionand extracted with ether.The ether extract is dried with anhydrous calcium sulfate, and, the.solvent; removed by distillation, yielding 16.4 g..(,86%). of2-di8thylaminoethyl alphaphenylalpha- (7-chloro-4 quinolyl) acetate.

The condensation described: in the previous paragraph can be carried outinthe absence of sodium, ut with sacrifice in yield 3.9.=%)..

The free basic esters are light orange-yellow oils, which recompose ondistillation. The monohydrochlorides of these compounds are readilyobtained by dissoving the bases in three volumes of acetone orisopropanol, adding slightly less than the calculated amount ofalcoholic hydrogen chloride, diluting with ether just to turbidity, andscratching or seeding to start crystal formation. Where necessary, thehydrochlorides are recrystallized from isopropanol or acetone. Thesehydrochlorides are stable white crystalline substances easily soluble inwater. Salts prepared in such a manner include: 2-diethylaminoethylalphaphenylalpha- (4- quinolyl) acetate hydrochloride, M. P. l36-l38.5C. (corr.); 2-diethylaminoethyl alpha-phenyl-alpha-(5-chloro-4quin0lyl)acetate hydrochloride, M. P. 178.3- l79.8 C. (corr.); andZ-diethylaminoethyl alphaphenyl-alpha- (7-chloroi-quinolyl) acetatehydrochloride, M. P. 159.6-160.6 C. (corr.).

Other basic esters are prepared by the above procedure using othertertiary-aminolkanols and other lower alkylalphaaryl-alpha-(4-quinolyl)- acetates. Such esters include:3-(1-piperidy1) propyl alpha- (4- chlorophenyl) alpha- 6,8- dichloro- 4-quinolyl) acetate; 5- diethylamino-Z- pentyl alpha-(3,4-dich1orophenyl)-alpha-(3-mitro--quinolyl) acetate; 2-(e-morpholinyD-ethyl alpha- (-methoxyphenyl) -alpha- (6-methoXy-4-quinolyDacetate; and the like.

V. N (tertiary-aminoalkyl) -aZpha-aryl-alpha- (4quin0Zg/Z)acetamides andsalts thereof These basic amides designated as VII in Chart I areprepared by the same procedure described under section IV for'therelated basic esters, but using lower aliphatictertiary-aminoalkylamines instead of tertiary-aminoalkanols. When thecondensations are run in the presence of a trace of sodium, the yieldsare low, being about 6%. Without the catalyst the yields run higher,ranging from 20 to 25 The yields are much higher (about 65% when anexcess of a given lower aliphatic tertiary-aminoalkylamine is used. Theproducts are crystallized from petroleum ether to give white crystallinesolids. The mono-hydrochlorides are prepared by the addition of slightlyless than the equivalent of alcoholic hydrogen chloride to anisopropanol or acetone solutionof the base. 1

Using Z-diethylaminoethylamine in the above procedure, the followingN-(2-diethylaminoethyl)-alpha-phenyl-alphai-quinolyl) acetamides andhydrochlorides thereof are formed: Where .the i-quinolyl radical is4-quinolyl, M. P. of base, l18.6ell9.6 C. (corr.) and MQP. of HCl salt,-112" 0.; where 5-chloro-4-quinolyl, M. P. of base, 92-93 C. andM; P. ofHCl salt, 99-.5-10I 'C.; "and where.i-chloroi-quinolyl, M. P. of base,134.6-1354" C. (corr.) and M- P. of I-ICl salt, 158- l59.2 C. (corr-).

Using other. lower aliphatic. tertiary-aminoalkylamines and other loweralkyl alpha-aryl-alpha- (4-quinolyDacetates in the above procedure thefollowing basic. amides. are formed: N- (3-(1- piperidyhpropyl lalpha-(4- chlorophenyl) a1- pha- (6,8-dichloro-4- quinolyhacetamide; N- (5-diethylamino 2- pentyl). alpha- (3,4 dichlorophenyl) -alpha- (3-nitro-4-quinolyl') acetamide; N--( 2-:(4-morpholinyl) ethyl)--alpha('4-methoxyphenyD- alpha- (6-rr1ethoxy-4- quinolyl)-acetami-de; N-methyl N- (Z-d-iethylaminoethyl) -alphar nyl lpha- (7- h 0r0-4 qinolyl) acetamide; andthelike. J .3.

' VI. 4-m'ylmethylquinolines These 4-substituted-quinolines are preparedby treating under various conditions the related alpha-arylalpha- (4-quinolyl) acetonitriles. 11- 1 lustrative of these reaction conditionsare the following procedures: Five parts by weight ofan alpha:arylalpha- (4'- quinolyl) acetonitrile and eigh t"parts by volume 'eachof concentrated sulfuric acid and water are refluxed vigorously for Onehour. Initially, carbon dioxide evolves in copious amounts. At the endof the heating period, the yellow solution is poured into amixture ofice and excess ammonium hydroxide.

The product which separates is taken. up'ina solvent such as ether, theextract dried over'anhydrous calcium sulfateja'ndthe solvent distilledto give a quantitative yield of pale y'ellowoil which solidifies onstanding. Recrystallization from petroleum ether gives the purifiedcrystalline 4-arylmethylquinoline. f y In another, and specific,preparation a solution of 5 g. of alpha phenyl alpha (7 chloro 4-quinoIyDacetonitrile, 8 ml. of concentratedsulfuric acid, 2 ml. ofwater, and ml. of methanol isrefluxed for 22 hours on a steam bath.Working up of the reaction mixture as described in the precedingparagraph yields a quantitative yield of the crude7-chloro-4-benzylquinoline,

which when recrystallized from petroleum ether, melts at 93.5-94 C.

Another means of preparing the 4-arylmethylquinolines of our inventionis illustrated by the following preparation of 7 chloro 4 --benzy1-quinoline: Hydrogen chlorideis passed for eight hours into a refluxingsolution of 5 g. of alphaphenyl alpha (7 chloro 4 quinolyl) acetonitriledissolved in 50 ml. of absolue ethanol. The solution is filtered whilehot to remove the ammonium'chloride which has separated, the filtratecooled, 20ml. of ether added, and after standing two days the whitesolid which separates is filtered. The product obtained is 4 g. ofimpure 7-chloro-4-benzylquinoline hydrochloride, M. P. 218-220 C. (withdecomposition), the structure of which is confirmed by converting intothe corresponding 7-chloro-4-benzylquinoline, which has propertiesidentical with the compound the preparation of which was described inthe previous paragraph.

Other 4-benzylquinolines prepared according to the above procedures fromthe related alphaphenyl alpha (4 quinolyl) acetonitrile include:4-benzylquinolihe, P. 52-525" 0. and mono-sulfate salt thereof, M. P.195-196 0.; 5-chloro-4-benzylquinoline, M. P. 48.6-49.2 C. (corn).

Using. other alpha-aryl-alpha-(4-quinoly1)- acetonitriles in the aboveprocedures the following 4-arylmethylquinolmes are obtained: 6,8-dichloro 4 (4 chlorophenyl) methylquinoline; 3 nitro 4 (3,4dichlorophenyl) methylquinoline; 6 methoxy 4 (4 methoxyphenyl)methylquinoline; and the like.

The above illustrated process of preparing 4-arylmethylquinolines of theformula QCHaA by heating the corresponding alpha-aryl-alpha-(4-quinolyl) acetonitriles in an acidic medium and some of the4-arylmethyl-halogenated-quinolines obtained thereby are disclosed andclaimed in our copending continuation application, Serial No. 231,672,filed June 14, 1951.

Quaternary derivatives of these 4-arylmethylquinolines are prepared bythe following method, which is similar to the general method describedby -Alekseevaiw. Geri. ChemSKUJS. 8.11%.) 10, 26311940) Cf. C.A'."34,-,.7291I(19.40) 743111011)- 4-benzylquinolin is .treated;with athirty percent excess of 'dimethyl'w'sulfate and the mixture warned on5a steam bath; I: The resulting viscous yellow oil is dissolved :in anequal volume ofwater and'an'excess ofa"50% .potassium iodide solutionadded. The yellow solid which forms. is filtered-off and dried in avacuum desiccator. .The product, obtained in quantitative yield, is;recrystallized by stirring'in 35. volumes of hot absolute ethanolfollowed by ice-cooling to give golden leaflets "of'7-chloro4-benzylquinoline methiodide, M. 1?. 2 29.2230.6 C. (corn)withdecomposition. Prolongedcontact with hot ethanol results inconsiderable decomposition of this quaternary salt.

I 4-Be'nzylquinoline .methiodide obtained ma alpha phenyl alpha (4quinolyDacetoaliphatic tertiary-amino radical, and .addition saltsthereof. I

2. A basic ester of the formula ocmmoooxs I where Q is a i-quinolylradical, A'is an aryl radi cal of the benzene series, X isv a, loweralkylene radical, and B is a lower aliphatictertiary-a mino radical, andaddition-salts thereof.

3. A basic amide of the formula QCH(A) CONHXB where Q is a 4-quinolylradical, A is an aryl radical of the benzene series, X is a loweralkylene radical, and B is a lower aliphatic tertiary-amino radical, andaddition salts thereof.

4. A basic ester of the formula QCH (CeHs) COOXB where Q is a 4-quinolylradical, X is a lower alkylene radical, and B is a lower aliphatictertiary-amino radical, and addition salts thereof.

5. A basic amide of the formula QCH (CcHs) CON HEB where Q is a4-quinolyl radical, X is a lower allwlene radical, and B is' a loweraliphatic tertiary-amino radical, and addition salts thereof- 6. Aprocess for preparing a basic compound of the formula QCH (A) COYECBwhere Q is a 4-quinolyl radical, A is an aryl radical of the benzeneseries, Y is a member of the group consisting of *0, NH, and N- (loweralkyl), X is a lower alkylene radical, and B is a lower aliphatictertiary-amino radical, which comprises reacting a lower alkyl ester ofthe formula QCH(A) COO- (lower alkyl) with a basic compound of theformula BXYH, where Q, A, B, X and Y have the meanings givenhereinabove.

7. A process for preparing a basic ester of the formula QCH(A) 000KBarea-27s where Q is a e-quinolyl radical, A is an aryl radical of thebenzene series, X is a lower alkylene radical, and B is a loweraliphatic tertiary-amino radical, which comprises reactingia loweralkylester of the formula QCH(A)'CO-O-(loweralkyl) with a basic alkylamine ofthe formula BXNHz, where Q, A, B and X have the meanings givenhereinabove.

9. A process for preparing a basic" ester of the formula QCH(CsH)COOXBwhere Q is a 4-quinolyl radical, X is a lower alkylene radical, and B isa lower aliphatic tertiary-amino radical, which comprises reacting alower alkyl ester of the formula QCH(C6H5) COO- (lower alkyl) with ,abasic alkanol'of the formula BXOH, where Q, B and X have the meaningsgiven hereinabove;

10. A process for preparing a basic amide of the formula QCH (Cal-I5)CON I-IXB where Q is a 4-quinoly-l radical,.X is a lower a1- kyleneradical, and B is a lower aliphatic tertiary-am-ino radical, whichcomprises reacting 'a lower alkyl'ester of the formula QCH(CsH5)'COO-(lower alkyl) with a basic alkylamine' of the formula BXNI-Iz, where Q,B, X and Y havethe meanings given hereinabov'e;

1 1. 2-diethylaminoethyl alpha phenyl alpha- 116 (7-chloro-4-quinolyl)acetate, and addition salts thereof.

l2. 2-diethylaminoethyl alpha phenyl alpha- '(5ch1oro-4-quinolyl)acetate, and addition salts thereof. 7

v 13. Z-diethylaminoethyl alpha-phenyl-alpha- (4-quinolyl)ac'etate, andaddition salts thereof.

14, N-(2-dithylaminoethyl) alpha phenylalpha-(7-chl0ro-4-quinoly1)acetamide, and addition' salts thereof.

15; N (2-diethylarninoethyl) alpha phenylalph'a-(5-ch1oro-4-quirioly1)acetamide, arid addition salts thereof. v

16. A process for preparing 2-diethylaminoethylalpha-phenyl-alpha:('7-ch1or0-4-quinoly1)- acetatewhich comprisesreacting a lower alkyl alpha-phenyl-alpha-(7-chloro-4-quinolyl) acetatewith 2-diethylaminoethanol.

17. A process for preparing 2-diethylaminoethyl alpha phenyl-alpha-5-chloro-4-quin'olyl acetate which comprises reacting a lower alkylalphapheny-l alpha-i5-chloro-4=quinolyl)'acetate withdiethylaminoethanol.

1 8-. A process forpreparing 2'-'d-i'ethylamino'- 'c't'lryl alpha'phenyl alpha (4-- quinolyl )'acetate which comprises reacting a loweralkyl alphaphenyl alpha (4- quinolyli acetate with 2diethylamihoethanol'. v e

191 A process for preparing N- (2-diethylami-iioethyl) -alphaphenylalpha- (-7- chloro-4-qu'ino- IyDacetamide which comprises reactinga lower alkyl alpha-phenyl-alp'ha (7-chloro-4-quinolyl) acetate With-2-diethylaininoethylamine.

20. A process for-preparing N- (Z-diethylaminoethyll-alpha phenyl alpha-(5 -chloro-4-'quinclyllracetam ide which-comprises reacting a loweralkyl alpha-phenyl-alph'a-(5-chloro-4-quiriolyl)- acetate: with2-diethylaminoethylamine.

ALEXANDER, SURREY. ROYAL A. CUTLER.

'No' references cited.

6. A PROCESS FOR PREPARING A BASIC COMPOUND OF THE FORMULA